In the United States, prostate cancer (PCa) is the most commonly diagnosed and second-most lethal cancer in men. Widespread prostate-specific antigen (PSA) screening has led to an increase in PCa incidence and a shift in stage at diagnosis with 90% of tumors now being localized at diagnosis. However, the determination of clinical features (PSA, clinical stage, and Gleason grade) alone has limited ability to identify patients at substantially elevated risk of PCa-specific mortality. A better understanding ofthe biology of lethal PCa and identification of novel markers of aggressive disease are urgently needed to develop effective therapeutic and preventive strategies. Excess body weight is consistently linked to PSA recurrence in numerous clinical studies, but its role in PCa-specific and total mortality in PCa patients remains unclear. Our intriguing preliminary findings on the relations of body mass index (BMI), C-peptide (a marker of insulin production), and adiponectin with fatal PCa support important roles of insulin/insulin-like growth factor (IGF) axis in pathways connecting energy balance and obesity to cancer progression and survival. In this application, we plan to extend this exciting work to comprehensively evaluate energetic factors and PCa-specific and all-cause mortality in men diagnosed with PCa, accounting for competing causes of death. These factors include adiposity (BMI, waist and hip circumference, and weight gain) and Type 2 diabetes (Aim 1), biomarkers (Cpeptide, insulin, proinsulin, proinsulin/insulin ratio, IGF-1, IGF binding protein-3, and adiponectin; Aim 2), and genetic variants related to beta-cell function, insulin production, insulin sensitivity, and obesity identified by published genome-wide association studies (GWAS) (Aim 3). dietary insulin demand (assessed by the Cpeptide score, insulin index, and insulin load; Aim 4), vigorous physical activity and the macro-level factor of neighborhood built environment (assessed by the county sprawl index, Aim 5). This cost-effective project uses a unique and well-characterized PCa patient cohort of U.S. male physicians with 30 years of complete followup for outcomes and assessment of both pre- and post-cancer exposures. Findings of these studies will provide new insights for the role of energy metabolism in PCa progression, guide the identification of novel cancer therapeutic targets, and aid in the development of cancer prevention strategies from urban planning to diet and lifestyle modification.